Th2‐oriented profile of male offspring T cells present in women with systemic sclerosis and reactive with maternal major histocompatibility complex antigens

Abstract

Objective. To characterize the cytokine production profile of male-offspring T cells reactive against maternal major histocompatibility complex (MHC) antigens present in the peripheral blood and/or skin from women with systemic sclerosis (SSc).Methods. T cell clones were generated from peripheral blood and/or skin biopsy specimens from 3 women with SSc of recent onset and from peripheral blood from 3 healthy women, all of whom had 1 male child. All clones were screened for their proliferative response in vitro to maternal MHC antigens by measuring 3 H-thymidine uptake and for their expression of Y chromosome by using fluorescence in situ hybridization. The concentrations of interferon-␥ and interleukin-4 (IL-4) released by T cell clones in response to maternal MHC antigens were evaluated in culture supernatants, using appropriate enzyme-linked immunosorbent assays.Results. Thirty-nine of 202 T cell clones generated from women with SSc and 11 of 312 from healthy women proliferated in vitro in response to maternal MHC antigens. Seven MHC-reactive T cell clones obtained from women with SSc and 1 obtained from healthy women exhibited the Y chromosome, thus indicating that the clones were derived from T cells of male offspring. All clones generated from male-offspring T cells of SSc women (but not from those of healthy women) produced significantly higher levels of IL-4 in response to stimulation with maternal MHC antigens than did all other clones generated from the same women. The other clones proliferated in response to maternal or allogeneic MHC antigens but did not exhibit the Y chromosome.Conclusion. Male-offspring T cells that are present in the blood and skin of women with SSc and react with maternal MHC antigens exhibit a Th2-oriented profile, supporting the possibility that a chronic graft-versus-host reaction attributable to longterm microchimerism plays a pathogenic role in SSc.

Is systemic sclerosis an antigen‐driven T cell disease?

“…The T cell clones derived from male offspring T cells of women with SSc were of the Th2 type and produced, in response to maternal MHC antigens, substantially higher levels of IL-4 than did all of the remaining T cell clones derived from the same women. In the remaining T cell clones, the Y chromosome was not detectable, although they responded by proliferation to maternal or allogeneic MHC antigens (137). These results demonstrate that male offspring T cells that are present in small proportions in the skin or in the peripheral blood of women with SSc are able to respond, under appropriate conditions, to maternal MHC antigens and produce Th2 cytokines (137).…”

“…In the remaining T cell clones, the Y chromosome was not detectable, although they responded by proliferation to maternal or allogeneic MHC antigens (137). These results demonstrate that male offspring T cells that are present in small proportions in the skin or in the peripheral blood of women with SSc are able to respond, under appropriate conditions, to maternal MHC antigens and produce Th2 cytokines (137). The long-term presence of these male offspring T cells in women with SSc supports the notion that long-term microchimerism, manifested as chronic GVHD, may play an important role in the pathogenesis of SSc (137).…”

“…Scaletti et al reported that 39 of 202 T cell clones derived from skin biopsy specimens or peripheral blood from 3 women with SSc, and 11 of 312 T cell clones derived from the peripheral blood of 3 healthy women, proliferated in response to maternal MHC antigens (137). All 6 women had a male offspring.…”

The role of the acquired immune response in systemic sclerosis

“…Initial observations suggested that T cells infiltrating the skin and other organs in SSc were functionally heterogeneous but preferentially polarized towards IFN-γ production and therefore belonging to the Th1-like subset [28]. With the development of more refined techniques and increased knowledge about T cell function, it has become more evident and widely documented that T cells secreting high levels of IL-4 (Th2-like subset) distinctly populate SSc tissues [9,12,25,70,82,99]. These comprise classical CD4+ T helper cells [70,99] but also CD8+ T cells [9] as well as T cells expressing simultaneously CD4 and CD8 and carrying both helper and cytolytic function, together with high production of IL-4 [82].…”

“…With the development of more refined techniques and increased knowledge about T cell function, it has become more evident and widely documented that T cells secreting high levels of IL-4 (Th2-like subset) distinctly populate SSc tissues [9,12,25,70,82,99]. These comprise classical CD4+ T helper cells [70,99] but also CD8+ T cells [9] as well as T cells expressing simultaneously CD4 and CD8 and carrying both helper and cytolytic function, together with high production of IL-4 [82]. More recently, CD8+ T cells characterized by high production of IL-13 and expression of GATA-3 have been detected within the repertoire of Btype 2^cells present in SSc peripheral blood and involved skin, particularly during early phases of the disease [35,36,72].…”